Disulfides of amino-substituted mercaptopyridine-1-oxide

ABSTRACT

Disulfide of amino-containing mercaptopyridine-1-oxide having particular utility as antimicrobial agents per se and in skin cleansing detergent compositions, shampoos, hair dressings, disinfectants, preservatives and the like.

This is a divisional of application Ser. No. 629,436 filed Nov. 6, 1975,now U.S. Pat. No. 4,048,181, issued 9-13-77.

This invention relates to substituted amino-containingmercapto-pyridine-1-oxide derivatives having both antibacterial andantifungal activity, methods of manufacturing these compounds andcompositions containing them.

The art is replete with antibacterial agents and varied compositionscontaining such agents. Mercaptopyridine-1-oxide, the alkali metal andheavy metal salts thereof and disulfides thereof are known to possessantibacterial and anti-fungal activity. They have been found useful in avariety of anti-fungus and anti-bacterial compositions inclusive of weedkilling plant or soil fungicides, nasal sprays, topical creams, topicaldusting powder, shampoos, textile preservatives, etc. However,mercaptopyridine-1-oxide compounds wherein a substituted amino radicalis attached to a carbon atom in the pyridine ring are not disclosed inthe prior art. It has been found that these novel compounds possess theproperty of wide-spectrum anti-bacterial and anti-fungal activity per seas well as when incorporated into compositions such as preservatives,disinfectants, skin-cleansing detergents, shampoos, hair dressings andthe like.

A particularly difficult medium for successful employment of ananti-microbial compound is the human scalp and the hair thereon. Due tocontinued secretions of sebum and perspiration and deposits of dust,grease and oils on the scalp, often in part at least attributable to theuse of preparations for treating the scalp and hair, particularlyfavorable conditions for the growth of microorganisms often prevail onthe scalp. Even if the hair and scalp are washed fairly frequently,growth of microorganisms there is generally faster than on most otherparts of the human body and consequently the actions of antimicrobialcompounds employed thereon are often ineffective. However, by the use ofthe compounds of this invention, good activity is obtained againstmicroorganisms commonly found in the scalp and frequently associatedwith the dandruff syndrome.

The present compounds may be used in solutions, emulsions orsuspensions, or as solids. They are usually in the form of aqueoussolutions and may be applied to sites on which growth of microorganismsis to be counteracted. For ease of application to such sites, they maybe included in various carrier compositions and are considered to beespecially useful in hairdressing preparations and in shampoos.

In accordance with the present invention there are provided novelderivatives of mercaptopyridine-1-oxide having the following structuralformula: ##STR1## wherein R is selected from the group consisting of anacyl R_(o) C═0, where R_(o) is a C₁ -C₆ alkyl, aryl selected from theclass consisting of naphthyl and benzyl, halosubstituted aryl, aralkyl,said alkyl having 1-6 carbons; an alkoxycarbonyl R_(o) OC═O, where R_(o)has the same meanings as above; a C₁ -C₆ alkanesulfonyl; anaralkanesulfonyl; an arenesulfonyl ArSO₂, wherein the aryl group may besubstituted by a C₁ -C₆ alkyl, alkoxy and/or a halo radical; R₁, R₂ andR₃ are independently selected from the group consisting of hydrogen,straight and branched chain C₁ -C₆ alkyl groups, aryl and aralkylgroups, wherein the aryl group may be a phenyl, napthyl and furyl andmay be substituted by a halo and/or a C₁ -C₆ alkyl group; R₄ is selectedfrom the group consisting of hydrogen, benzyl, and a metal from thegroup consisting of sodium, potassium, lithium, zinc, calcium,magnesium, manganese, chromium, iron, copper, tungsten, nickel, barium,strontium, a quaternary ammonium ion R₅ R₆ R₇ R₈ N⁺ wherein R₅ and R₆are each hydrogen or C₁ -C₃ alkyl, R₇ is hydrogen, C₁ -C₃ alkyl, benzylor C₁₂ -C₂₂ alkyl and R₈ is hydrogen, C₁ -C₃ alkyl or C₁₂ -C₂₂ alkyl,and the group: ##STR2## Related disulfides have the formula: ##STR3##Salts of the mercaptopyridine-1-oxides have the formula: ##STR4##wherein R, R₁, R₂ and R₃ have the same meanings as in formula I, M is amono-, di-, or trivalent metal selected from the group consisting ofsodium, potassium, lithium, zinc, calcium, magnesium, manganese,chromium, iron, copper, tungsten, nickel, barium and strontium, and n isa number from 1 to 3. Specific examples are:

2-acetamido-6-mercaptopyridine-1-oxide,

2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-propionamido-6-mercaptopyridine-1-oxide,

2-butanoamido-6-mercaptopyridine-1-oxide,

pentanoamido-6-mercaptopyridine-1-oxide,

2-hexanoamido-6-mercaptopyridine-1-oxide,

2-methoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-propoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-butoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-pentoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-hexoxycarbonylamino-6-mercaptopyridine-1-oxide,

2-methanesulfonylamino-6-mercaptopyridine-1-oxide,

2-ethanesulfonylamino-6-mercaptopyridine-1-oxide,

2-propanesulfonylamino-6-mercaptopyridine-1-oxide,

2-butanesulfonylamino-6-mercaptopyridine-1-oxide,

2-pentanesulfonylamino-6-mercaptopyridine-1-oxide,

2-hexanesulfonylamino-6-mercaptopyridine-1-oxide,

2-benzenesulfonylamino-6-mercaptopyridine-1-oxide,

sodium or zinc salt of 2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide,

sodium or zinc salt of 2-acetamido-6-mercaptopyridine-1-oxide,

bis[2-(6-ethoxycarbonylamino-1-oxopyridyl)] disulfide,

2-acetamido-3(4 or 5)-methyl-6-mercaptopyridine-1-oxide,

2-ethoxycarbonylamino-3(4 or 5)ethyl-6-mercaptopyridine-1-oxide,

2-propionamido-3(4 or 5)-n-butyl-6-mercaptopyridine-1-oxide,

2-butanoamido-3(4 or 5)-methoxy-6-mercaptopyridine-1-oxide,

2-pentanoamido-3(4 or 5)-ethoxy-6-mercaptopyridine-1-oxide,

2-hexanoamido-3,5-dimethyl-6-mercaptopyridine-1-oxide,

2-methoxycarbonylamino-3(4 or 5)-methyl-5(3 or4)ethyl-6-mercaptopyridine-1-oxide,

2-propoxycarbonylamino-3,5(or 3,4)-dimethoxy-6-mercaptopyridine-1-oxide,

2-butoxycarbonylamino-3,4,5-trimethyl-6-mercaptopyridine-1-oxide,

2-toluenesulfonylamino 6-mercaptopyridine-1-oxide,

cetyl trimethyl ammonium salt of 2-acetamido-6-mercaptopyridine-1-oxide,

cetyl trimethyl ammonium salt of any of the citedmercaptopyridine-1-oxides,

triethyl octadecyl ammonium salt of the cited mercaptopyridine-1-oxidecompounds,

myristyldimethyl benzyl ammonium salt of the citedmercaptopyridine-1-oxides,

dimethyl dilauryl ammonium salt of above namedmercaptopyridine-1-oxides,

2-acetamido-3(4 or 5)-phenyl-6-mercaptopyridine-1-oxide,

2-ethoxycarbonylamino-3(4 or 5)-furyl-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-napthyl-4(3 or5)methyl-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-bromophenyl-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-chlorophenyl-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-(trichlorophenyl)-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-chlorobenzyl-6-mercaptopyridine-1-oxide,

2-acetamido-3(4 or 5)-(dichlorobenzyl)-6-mercaptopyridine-1-oxide,

2-p-chlorobenzamido-6-mercaptopyridine-1-oxide,

2-benzamido-6-mercaptopyridine-1-oxide,

2-phenoxycarbonylamino-6-mercaptopyridine-1-oxide,

These mercaptopyridine-1-oxide derivatives are generally prepared inthree steps: Step 1-Forming the substituted aminobromopyridine byreacting 2-amino-6-bromopyridine with a reactant containing thesubstituent R. In lieu of the 2-amino-6-bromopyridine reactant, thepyridine nucleus may have substituents on the 3,4 or 5 carbons from theclass consisting of C₁ -C₆ alkyl groups; aryl groups such as phenyl,napthyl furyl, C₁ -C₆ alkyl and/or halo-substituted aryl groups; and C₁-C₆ aralkyl groups, wherein the aryl group has the same definition asabove.

The lower aliphatic acid anhydride or acid halide such as the chlorideor bromide containing 1-7 carbon atoms is suitable in the formation ofthe acylamino derivatives. Examples of these reactants are aceticanhydride, acetyl chloride, propionic acid chloride, propionic acidanhydride, butyric acid anhydride, butyric acid chloride, valeric acidanhydride, valeric acid chloride, hexanoic acid anhydride, heptanoicacid anhydride, heptanoic acid chloride and the like. The correspondingacylamino-bromo-pyridine is obtained. The acid anhydride or acidchloride, being liquid, is used both as the reactant and solvent for thereaction. The alkoxycarbonylamino-bromopyridine is obtained by utilizinga lower alkyl halo-formate inclusive of the chloro- and bromo-formatesas the reactant in lieu of the acid anhydride or acid halide. Suitablehalo-formates include methyl chloroformate ##STR5## ethyl chloroformate,propyl chloroformate, butyl chloroformate, hexyl chloroformate, pentylchloroformate, and the corresponding bromo-formates. Similarly the C₁-C₆ alkanesulfonylamino-bromopyridines may be obtained by using a loweralkanesulfonyl (RSO₂) containing reactant such as an alkanesulfonic acidanhydride or acid chloride. Likewise, the arenesulfonylamino-bromopyridine can be obtained by using an arenesulfonyl ##STR6##halide or other reactive arenesulfonyl compound.

Step 2: The above reaction product is oxidized with an organic peracidsuch as peracetic acid, m-chloroperbenzoic acid and the like, to formthe corresponding amino-substituted pyridine-1-oxide.

Step 3: Forming the mercaptopyridine-1-oxide compound by reacting theamino substituted pyridine-1-oxide compound with an alkali metalhydrosulfide such as sodium hydrosulfide. The respective salts thereofare prepared by reacting the mercapto derivative with sodium hydroxide,sodium methoxide, zinc nitrate or any other metal salt desired. Thedisulfides are prepared by reacting the mercapto derivative with iodine,potassium triiodide or dilute hydrogen peroxide or other oxidizingagent.

The amino derivatives of mercaptopyridine-1-oxide may be generallyprepared by reacting a 2-amino-6-bromopyridine compound with an excessamount of acid anhydride or acid halide containing the R substituent, inthe presence of a suitable solvent such as acetic anhydride, glacialacetic acid, at elevated temperatures of about 50°-75°, preferably at55°-60° C, for about 30 minutes to five hours, with continuous agitationto form the corresponding 2-acylamino-6-bromopyridine, which may bepurified by recrystallization from benzene. Another method of preparingthe amino derivative of 6-bromopyridine comprises reacting a2-amino-6-bromopyridine with an excess amount of an alkyl haloformatecontaining the R constituent in the presence of a suitable solvent suchas pyridine, while cooling to a temperature of about 15°-30° C(exothermic reaction) with continuous agitation, for a period of about30 minutes, to obtain the corresponding2-alkoxycarbonylamino-6-bromopyridine, which may be purified byrecrystallization from an aqueous methanol solution. The resultantpyridine compound, dissolved in a suitable solvent such as acetic acid,benzene, chloroform (as determined by the oxidizing agent), issubsequently oxidized with an excess amount of peracid such asperacetic, perbenzoic, chloroperbenzoic acid, at elevated temperaturesof about 50°-75° C for about 3 to 24 hours, with continuous agitation toform the pyridine-1-oxide derivative, which may be purified byrecrystallizing from propanol, cyclohexane, chloroform, or othersuitable solvent. The resultant pyridine-1-oxide compound is reactedwith an excess amount of an aqueous hydrosulfide salt at elevatedtemperatures of 50°-75° C, preferably 60° C, for a period of 2 to 5hours, to form the corresponding mercaptopyridine-1-oxide compound,which may be purified by recrystallization from propanol, aqueousethanol and the like.

The salts of the amino-substituted mercaptopyridine-1-oxides areprepared by neutralizing the aforesaid mercaptopyridine-oxides with anaqueous solution of a suitable base to a pH of about 5-8, at roomtemperature, and subsequently adding an aqueous solution of the desiredmetal or quaternary ammonium salt.

The disulfides are prepared by reacting theamino-substituted-mercaptopyridine-1-oxide compound per se or the sodiumsalt thereof with an oxidizing agent such as potassium triiodide,iodine, or hydrogen peroxide, in an aqueous medium and at roomtemperature.

The benzylthio derivative of the amino-substituted pyridine-1-oxide isprepared by reacting the amino-substituted-6-bromo-pyridine-1-oxide withbenzyl mercaptan in a suitable solvent such as methanol containingsodium methoxide, by heating to a temperature of about 55°-80° C forabout two hours, with continuous agitation. The resultant benzylthioderivative may be purified by recrystallization from ethyl acetate andcyclohexane.

More specifically, the mercapto pyridine-1-oxide derivatives of theinstant invention are prepared from known starting materials.2-amino-6-bromopyridine which may be prepared by hydrogen bromideinduced cyclization of 3-hydroxyglutaronitriles, a method described inU.S. Pat. No. 3,096,337, or by any other known process, is dissolved inan excess amount of acetic anhydride and heated at 70° C for 45 minutesand the excess acetic anhydride is hydrolyzed by the addition of 300 ml.water, to give a substantially quantitative yield (95%) of2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0°C. The 2-acetamido-6-bromopyridine is oxidized by heating a solutionthereof in glacial acetic acid with an excess of peracetic acid at 70° Cfor 2 hours and at 55° C for 19 hours. The reaction mixture is dilutedwith 1600 ml. water and concentrated in vacuum, unreacted materialremoved by filtration, and the solvent evaporated from the filtrate,giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide whichis purified and recrystallized from 2-propanol to yield fine whiteneedles having a melting point of 180.0°-180.5° C. The mercaptoderivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared byreaction with an excess of sodium hydrosulfide (1M NaSH) in anaqueous-ethanol medium while stirring for 5 hours at 60° C and overnightat room temperature, adding concentrated hydrochloric acid dropwise tothe cold yellow solution and collecting the light yellow solid byfiltration, purifying by recrystallization from 2-propanol and obtainingpale yellow crystals having a melting point of 172.8°-173.5° C. A 79%yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with theaforedefined process.

The alkali metal salt of 2acetamido-6-mercaptopyridine-1-oxide isprepared by alkalization with a base such as sodium hydroxide, orpotassium hydroxide, or ammonium hydroxide or the salt of the alkalimetal with a weak acid (e.g., sodium carbonate) in an aqueous oraqueous-alcoholic medium. Various other metal salts, such as alkalineearth metals, zinc, etc. of instant mercaptopyridine-1-oxides may beobtained in yields of 65-95% by dissolving the amino substitutedmercapto pyridine-1-oxide compound or the sodium salt thereof in water,adjusting the pH to about 5, adding an aqueous solution of the desiredmetal salt, (e.g., metal nitrate, halide, sulfate, etc.), purifying theprecipitate by successively washing with water, ethyl alcohol and/orethyl ether.

The reactions described above are illustrated by the followingequations: ##STR7##

For clarity of presentation, the above description of methods of makingthe invented compounds has been given with respect to a particularstarting material and corresponding derivatives thereof. However, itmust be realized that such methods are also applicable to reactionsutlizing different starting materials and effected by differentreagents, which are equivalent in their activities to those described.Thus, instead of utilizing 2-amino-6-bromopyridine as the startingmaterial, compounds having either branched or straight chain C₁ -C₆alkyl groups or aryl groups such as phenyl, napthyl, furyl, C₁ -C₆ alkyland/or help substituted aryl groups or C₁ -C₆ aralkyl groups whereinsaid aryl group is as aforedefined, bonded to the pyridine nucleus atthe 3-, 4-, and/or 5- position, may also be employed as the startingmaterial. Similarly, the bromide anion may be replaced by anothernegatively charged inorganic or organic group such as chlorine,fluorine, or iodide, with the bromide and chloride being preferred.Catalysts may be used, if desired. The solvents to be employed will besuch as are conducive to dissolving the reagents and which areunaffected by the reaction.

The salt of the substituted amino-mercaptopyridine-1-oxide may beconverted to the corresponding mercaptopyridine-1-oxide compound bytreatment with any suitable chemical for removing the salt-formingcation and replacing it with hydrogen. Thus, usually an aqueous solutionof an acid, preferably a dilute solution of a strong inorganic acid suchas hydrochloric acid or sulfuric acid, may be used to precipitate theamino-mercaptopyridine-1-oxide compound. The stoichiometric quantity ofacid, plus or minus 20%, will normally be employed and its dilution willusually be such that the normality is from 1 to 6 Normal. Of course,variations may be made in the types of acid and the concentrationsemployed, provided that sufficient acid is used to convert the salt tothe acid form. Other salts of the amino-substitutedmercaptopyridine-1-oxides may be obtained by treatment of a soluble saltthereof with a soluble metal, ammonium or quaternary ammonium or othersuitable inorganic or organic salt. If the alkali metal salt is moresoluble, it will often be possible to convert to other salts, such asheavy metal salts, merely by addition of a soluble heavy metal salt tothe alkali metal salt of the amino-substituted mercaptopyridine-1-oxide,preferably in aqueous solutions. Again, it is preferred to employapproximately stoichiometric proportions of such salt and thecorresponding alkali metal salt of said mercaptopyridine-1-oxide, butvariations usually plus or minus 10 to 20% from stoichiometricproportions, are also useful. Among the salts that may be made from thealkali metal salts, e.g., the sodium, potassium and lithium salts of theacylamino or alkoxycarbonylamino mercaptopyridine-1-oxide, are the zinc,calcium, magnesium, manganese, chromium, iron, copper, tungsten, nickel,barium, strontium, ammonium and quaternary ammonium, e.g.,cetyltrimethyl ammonium, triethyloctadecyl ammonium, myristyl dimethylbenzyl ammonium, methyl dilauryl ammonium, ethyldimethylstearylammonium, benzyldimethylstearyl ammonium, trimethylstearyl ammonium,dimethylpropyl myristyl ammonium, etc. The salts that may be employedinclude the corresponding chlorides, bromides, iodides, sulfates,phosphates, carbonates, borates, nitrates, acetates, citrates,propionates, phenates, and the other useful water soluble salts.

From the substituted amino mercaptopyridine-1-oxides, there may beproduced the corresponding bis[6-(2-substituted amino-1-oxopyridyl)]disulfide by oxidation. In such oxidation as shown by the equations,hydrogen atoms adjacent to the sulfur of the correspondingmercaptopyridine-1-oxide are removed, to be combined with oxygen to formwater. Thus, the sulfur atoms bond together, forming the disulfide. Suchoxidation may be effected by any suitable means, preferably utilizingpotassium triiodide, iodine, hydrogen peroxide, or other oxidizingagent. The substituted-amino mercaptopyridine-1-oxide compound isusually dissolved or suspended in a suitable solvent which is capable ofmaintaining its liquid form during the reaction. The proportion ofreactant in solvent is not considered to be critical. The preferredsubstituted amino groups include the acylamino-, and thealkoxycarbonylamino radicals.

The compounds produced, whether in the form of thesubstituted-amino-mercaptopyridine-1-oxide compound, the disulfidethereof, or a salt thereof, exhibit exceptionally good antimicrobialproperties. They are found to have wide-spectrum antibacterial activityand to be effective in killing bacteria and in limiting the growths of avariety of organisms. Particularly, they are very effective against theorganism pityrosporum ovale, commonly found on the scalp and frequentlyassociated with the dandruff syndrome. A 10% suspension of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide in 95% ethanol has beenfound to inhibit the growth of P. ovale in an amount as low as 1.9micrograms per milliliter. Similarly, a 1.0% suspension of the disulfideof the above compound in 95% ethanol inhibits the growth of P. ovale inan even lower amount, namely, less than 0.5 micrograms er milliliter.Whereas from 1.9 to 12.5 micrograms per milliliter of the zinc salt of2-mercaptopyridine-1-oxide (a known antimicrobial agent) is required toinhibit the growth of P. ovale. Thus, it is apparent that the acylaminosubstituted mercaptopyridine oxides of instant invention exhibit greatertoxicity against Pityrosporum ovale, an organism commonly found withhair and scalp associated with dandruff. Often, when microorganisms aregrowing in such an environment, it is difficlt to have an antimicrobialcompound be effective against them, due to the inhibiting action of thegrease or lipophilic material on the bactericide. Such inhibition maybeeither chemical or physical, whereby the lipophile reacts with theantimicrobial compound to change it to a less effective compound, or inwhich it prevents contact of the antimicrobial product with themicroorganism.

In addition to the excellent utilities of the present compounds in suchdifficult environments, which are encountered on human or animal bodiesand on the scalp or hair, it is found that these compounds arecompatible with a wide variety of compositions and media in which theyare employed. Thus, aqueous and alcoholic solutions of these compoundsare useful, as are cosmetic preparations containing them, whether basedon aqueous or lipophilic media or combination of both such phases. Forexample, the present antimicrobial compounds may be used in cosmetics ordetergents including liquid, solid, and semi-solid paste, cream orgelatinous preparations. They may be employed in soaps, shampoos,hairdressings, dusting powders or talcs, feet powders, "aerosol" spraypreparations of various types, anti-perspirants, deordorants,antiseptics and many other materials intended for cleaning, grooming orsanitizing purposes. Perhaps the most preferred compositions cntainingthese compounds are those which are used in contact with human hair orscalp, such as shampoos and hairdressings. Water or alcohol-solubleactive ingredients are necessary for the formulation of transparentanti-dandruff hair products. The solubility at pH 7 of certain ofinstant substituted-amino mercaptopyridine-1-oxide compounds and thesodium salts thereof exceeds 0.5-1% and thus is suitable for hairdressings and shampoos. Others, such as the zinc salts of thesubstituted amino-mercaptopyridine-1-oxides are insoluble and thusamenable to formulation only in opaque products. After use of suchpreparations, it appears that the effects of the present anti-microbialcompounds are long lasting. The substituted aminomercaptopyridine-1-oxides, disulfides, and salts thereof, are effectiveagainst such potent gram-positive organisms as Staphylococcus aureus,Streptococcus mitis, gram negative bacteria such as Eschericha coli,Pseudomonas aeruginosa, as well as against the yeasts such as Candidaalbicans and Pityrosporum ovale and the molds Trichophytonmentagrophytes and Aspergillus niger.

A high level of activity against the mold Trichophyton mentagrophytes,and the yeast most frequently associated with dandruff, Pityrosporumovale, is exhibited by the compounds of instant invention. Such effectsof these compositions have not been noted before and the activeantibacterial compounds and compositions containing them have not beentaught or suggested by the prior art.

In addition to the new compounds and methods for their manufacture, alsowithin the present invention, are cosmetic and detergent compositionscontaining such compounds as active wide-spectrum antimicrobialingredients, and antimicrobial uses of the compounds and suchcompositions. It is considered that the present antimicrobials areuseful in a wide variety of cosmetic preparations, includinghairdressings, hair tonics, hair waving solutions, hair dyes, bleaches,rinses, face creams, face powders, foot powders, body lotions, tanningagents, antiperspirants, sunscreens, personal deodorants, makeuppreparations, bath oils, facial treatments, astringents, shaving creams,after-shave lotions and various other preparations for treatment of thehair or skin, in which antibacterial or antifungal acitivity is useful.Among the detergent compositions which can usefully include the presentantimicrobial compounds are bar soaps, liquid soaps, soap shampoos,synthetic detergent shampoos, heavy duty synthetic organic detergents,inorganic detergent salts, pre-soak compositions, which may includeenzymes, softeners, dishwashing products, synthetic detergents intendedfor washing hard surfaces, e.g., janitorial detergents, floor cleaningcompositions and other detergent-related products such as wear-removers,organic solvent solutions of surface active materials, compositions foremployment with steam cleaning machinery, car washes, and sterilizingpreparations.

The cosmetic compositions may contain from 0.1 to 99% of activeingredients for the primary purpose for which they are intended togetherwith from 0.1 to 10%, preferably from 0.1 to 3%, of a compound of thepresent invention. Usually the cosmetics will contain from 1 to 100% ofan aqueous or an oily phase or a solid material (foot and face powders),and sometimes, as in the case of emulsions, will contain both aqueousand oily phases, often with a surface active material to aid inemulsification. Such surface active agents may be anionic, nonionic,cationic or amphotoeric and are usually present in emulsified cosmeticsin proportions of frm 0.5 to 20% thereof.

Although the most preferred embodiments of the invention, hairdressingsor other preparations intended for application to the hair, may beessentially lipophilic, essentially hydrophilic or emulsions, and mayeven be inert powders, the present compounds may be employed in any suchmedium. If the medium is lipophilic, there will usually be present from50 to 99% of oil, such as mineral oil, lanolin, lanolin derivatives orother lipophilic materials, together with one or more of the presentcompounds. A solvent, e.g., a lower alkanol such as ethanol orisopropaneol, may also be used to thin the lipophilic phase to make iteasier to apply. It will usually be from 5 to 80% of the cosmetic. Ifthe preparation is hydrophilic, it will usually contain from 50 to 99%of water, sometimes with 5 to 50% lower alkanol solvent associatedtherewith, plus one or more of the present anti-microbial compounds. Theemulsions may have from 1 to 99%, usually from 20 to 80% of eitherlipophilic or hydrophilic materials, with essentially the balancethereof being of the other type. The various active ingredients utilizedto give the different cosmetic preparations their desired properties arewell known and are exhaustively described in the text by Edward Sagarin,Cosmetics Science and Technology (1957), and therefore will not belisted here. However, for example, it is mentioned that with respect tohairdressings, ordinarily a mineral oil and lanolin will be employed tocondition the hair and facilitate its taking of waving and combing.

Antiperspirants will normally contain an active chemical for suchpurpose, such as aluminum chlorhydrate. Dusting powders will normally bebased on talc, silica or other special form of such materials, such aspyrogenic silica. Skin creams or lotions will usually include stearicacid or other cold cream ingredients. The proportions of such activematerials as was previously mentioned, may be varied widely, as is knownin the art, and may constitute from 0.1 to 99% of the total composition.

The detergent compositions in which the present antimicrobial compoundsare useful may be either built or unbuilt products and may be based onanionic, cationic, nonionic and/or amphoteric surface active compounds.These are well known and are described in the text by Schwartz, Perryand Berch, Surface Active Agents and Detergents, Volume II, (1958),particularly at pages 321 and 621-625. Most frequently, the detergentsemployed will be anionic detergents, including the common higher fattyacid soaps of alkali metals and the synthetic anionic organic detergentsalts such as those which are currently commercially used.

As examples of the anionic synthetic organic detergents there may bementioned the C₁₀ -C₂₀ alkane sulfonates, C₈ -C₁₈ fatty acidmonoglyceride sulfates, linear C₁₀ -C₁₅ alkyl benzene sulfonates, C₈-C₁₈ fatty acid soaps, C₁₀ -C₁₅ alkyl polyoxyethylene (1-5EO) sulfates,hydroexyalkylene sulfonates, C₈ -C₁₈ alcohol sulfates, salts of C₁ -C₃alcohol esters of C₈ -C₁₈ sulfofatty acids, C₈ -C₁₂ alkylphenolpolyethoxy ether sulfates, C₈ -C₁₈ acyl sarcosinates, C₈ -C₁₈ acylesters of isothionates and C₈ -C₁₈ acyl N-methyl taurider, to name onlya few. The salt-forming metals or other suitable salt-forming radicalsfor the detergents are preferably alkali metal, such as potassium orsodium, but alkaline earth metals such as calcium and magnesium andammonium, alkylamine, and alkanolamine salts may also be used. Somespecific examples of these detergents are sodium lauryl sulfate; sodiumlinear tridecyl benzene sulfonate, triethanolamine lauryl sulfate;sodium or potassium coconut oil tallowsoaps; sodium lauryl sulfonate;potassium hexadecylnaphthalene sulfonate; lauryl alcohol ethylene oxidesulfate comprising four ethoxy groups per molecule; potassium stearylglyceryl ether sulfonate; sodium lauroyl sarcosinate; and magnesiummethylene tauride.

Among the nonionic surface active agents are the condensation productsof C₈ -C₁₂ alkylated phenols with ethylene oxide, C₈ -C₁₈alkylthioethanols with ethylene oxide, C₈ -C₁₈ fatty alcohols withethylene oxide and polypropylene glycols or other polyols with ethyleneoxide, wherein from 5 to 30 moles of ethylene oxide are associated withthe hydrophobic moiety.

Among the cationic surface active materials are N-2-aminoethyl-higheralkyl amines; N-2-aminoethyl higher fatty acid amides; and quaternaryammonium compounds wherein an alkyl group is of 12 to 18 carbon atomsand other groups attached to the nitrogen are alkyls of 1 to 3 carbonatoms. Among such are ethyldimethylstearyl ammonium chloride; benzyldimethylstearyl ammonium chloride; and trimethylcetyl ammonium bromide.

The amphoteric detergents, useful herein, are generally water solublesalts of derivatives of aliphatic amines which contain at least onecationic group which may be part of a heterocyclic ring, and an anionicwater-solubilizing carboxyl, sulfo, sulfate, phosphate or phosphorogroup in their molecular structure. Examples of suitable amphotericdetergents include the C₈ -C₁₈ alkyl beta-aminopropionates, RN(H)C₂ H₄COOM; the C₈ -C₁₈ alkyl beta-iminodipropionates, RN(CH₂ H₄ COOM)₂ ; theC₈ -C₁₈ alkyl and hydroxyalkyl taurinates, RN(CH₃)C₂ H₄ SO₃ M; and longchain (C₇ -C₁₇) imidazole derivatives having the following formulas:##STR8## wherein W is selected from the group of

    ROH, R.sub.2 COOM, and R.sub.2 OR.sub.2 COOM,

y is selected from the group containing OH⁻, R₃ OSO₃ ⁻ ; R₂ is analkylene or hydroxyalkylene group containing 1 to 4 carbon atoms; and Mis a water soluble cation such as sodium, potassium, ammonium oralkylolammonium. Preferred detergents are sodium N-laurylbeta-amino-propionate, disodium N-lauryl iminodipropionate, and thedisodium salt of 2-lauryl-cyclomidium-l-hydroxyl, 1-ethoxy-ethanoicacid, 1-ethanoic acid.

Zwitterionic detergents such as the betaines and sulfobetaines havingthe following formula are also useful: ##STR9## wherein R is an alkylgroup containing about 10 to 18 carbon atoms, R₂ and R₃ are each C₁ -C₃alkyl, R₄ is an alkylene or hydroxyalkylene group containing about 1 to4 carbon atoms, and X is C or S:C. The alkyl group can contain one ormore intermediate linkages such as amido, other or polyether linkage, ornon-functional substituents such as hydroxyl or halogen which do notsubstantially affect the hydrophobic character of the group. When X isC, the detergent is called a betaine; and when X is S:O, the detergentis called a sulfobetaine or sultaine. Preferred betaine andsulfobetaines are 1-(lauryl dimethylammonio)acetate, 1(myristyl dimethylammonio)propane-3-sulfonate, and 1-(myristyldimethylammonio)-2-hydroxy-propane-3-sulfonate.

In the built detergents, water soluble inorganic salt builders ororganic builders are present to assist in dispersing peptizing,sequestering, and alkalizing, whereby detergency is increased. Amongthese are the pyrophosphates, tripolyphosphates, silicates, borates,carbonates, sequisiicates and other water soluble alkaline salts, forwhich the salt-forming metal is usually an alkali metal, such as sodiumor potassium.

Generally, in the detergent compositions, the proportion of detergentwill be from 5 to 99% by weight and preferably there will be presentfrom 10 to 50% thereof in both built and unbuilt compositions. Thebuilder salts, when present, will normally be from 15 to 60% by weightof the composition and the active antimicrobial compound will be from0.1 to 10% thereof, preferably from 0.1 to 5% thereof and most oftenwill be from 0.5 to 3% of the total product. Such compositions willusually include an adjuvant or mixture thereof, in an amount from 0.1 to25% by weight. Such adjuvants include perfumes, dyes, bleaches,softening agents, anti-redeposition agents, emollients, and brighteners.In the preferred detergents, which are essentially unbuilt shampoopreparations, there will be present from 5 to 33% of soap or syntheticorganic detergent or mixture thereof, from 0.1 to 5% of antimicrobialcompounds and from 1 to 20% of various adjuvants, such as thickeners,foaming agents, perfumes, coloring materials, and conditioning agents.The balance will be an aqueous medium such as water or a mixture ofwater with 5 to 25% by weight of a C₁ -C₃ alkanol, if desired.

The present antimicrobial preparations, cosmetics or detergents are usedin accordance with normal techniques. Thus, to sterilize or makeantibacterial a particular surface, a suitable solution of the presentamino derivatives of mercaptopyridine-1-oxide or other compound of thisinvention may be applied to the surface and allowed to remain there orit may be removed by rinsing after a suitable time. The detergents andcosmetics are used in normal fashion. The amino derivatives ofmercaptopyridine-1-oxide, disulfides thereof, and salts thereof, act tokill bacteria and fungi while on the surface which is a locus thereof.Various of the present compounds are found to be especially usefulagainst bacteria and fungi which normally are resident in the hair, suchas Staphylococcus aureus and Pityrosporum ovale.

The following examples are given to illustrate specific preferredembodiments of this invention. Clearly, the invention is not limitedthereto. All temperatures are given in degrees Centigrade and all partsare by weight, unless otherwise indicated.

EXAMPLE 1 Preparation of 2-acetamido-6-mercaptopyridine-1-oxide

Step 1: 20 g (0.116 mole) of 2-amino-6-bromopyridine was dissolved in140 ml. acetic anhydride and heated at 70° C for 45 minutes.2-Acetamido-6-bromopyridine was isolated by filtration as white flakes,m.p.=159.2°-160.0° C, in 68% yield. The excess acetic anhydride presentin the reaction mixture was hydrolyzed by the addition of 300 ml. waterto the filtrate; the reaction mixture was agitated and an additional 27%yield of 2-acetamido-6-bromopyridine was collected by filtration, givinga 95% yield of reaction product, 2-acetamido-6-bromopyridine which wasrecrystallized from benzene.

Elemental Analysis:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated: 39.10      3.28       13.02                                       Found:      39.12      3.24       13.09                                       ______________________________________                                    

Infrared characteristics (IR), absorption wave length in microns: N--H;3.13, 3.31; C═O; 6.02.

Step 2: 23.4 gms (0.109 mole) of 2-acetamido-6-bromopyridine wasdissolved in 200 ml. of glacial acetic acid containing 27.6 ml (0.218mole) of 7.9M peracetic acid and the solution was heated at 70° C for 2hours and at 55° C for 19 hours. The reaction mixture was diluted with1600 ml water and the solution was then concentrated in vacuo to 550 ml.8.6% of unreacted-2-acetamido-6-bromopyridine was removed by filtration.The solvent was evaporated from the filtrate giving an 83% yield ofimpure 2-acetamido-6-bromopyridine-1-oxide which was purified bytreatment with activated charcoal to remove the yellow impurity andsubsequently recrystallized from 2-propanol. A second recrystallizationfrom 2-propanol gave fine white needles, m.p=180.0°-180.5° C.

Elemental Analysis:

    ______________________________________                                                    C       H         N                                               ______________________________________                                        Calculated:   36.39     3.05      12.12                                       Found:        36.20     3.00      11.84                                       1H: N--H; 3.08                                                                   C=O; 5.92                                                                     N--O; 8.23                                                                 ______________________________________                                    

Step 3: 2 gms (0.0087 mole) of 2-acetamido-6-bromopyridine-1-oxide wassuspended in 35 ml (0.035 mole) of 1M aqueous sodium hydrosulfide and 30ml of ethanol and agitated at 60° C for 5 hours and at room temperatureone night. Concentrated hydrochloric acid was added dropwise to the coldyellow solution and the precipitated solid filtered, giving a 79% yieldof 2-acetamido-6-mercaptopyridine-1-oxide. This impure product waspurified by recrystallization from 2-propanol and hot filtration toremove a small amount of contaminating sulfur to give pale yellowcrystals, m.p.=172.8°-173.5° C.

    ______________________________________                                        Elemental Analysis:                                                                        C        H        N      S                                       ______________________________________                                        Calculated:  45.64    4.38     15.21  17.40                                   Found:       45.32    3.64     15.48  16.84                                   I.R.: N--H; 3.09                                                                 C=O; 5.91                                                                     N--O; 8.31                                                                 ______________________________________                                    

EXAMPLE 2

Preparation of the zinc salt of 2-acetamido-6-mercaptopyridine-1-oxide:0.50M aqueous sodium hydroxide was added to 0.251g (0.00136 mole) of2-acetamido-6-mercaptopyridine-1-oxide, as prepared in Example 1, in 3ml of water until a pH of 5 was obtained by said solution. 4.0 ml(0.0080 mole) of 0.20M aqueous zinc nitrate was added to said solution,whereby the zinc salt of 2-acetamido-6-mercaptopyridine-1-oxideprecipitated immediately. Upon filtration, an 84% yield of the zinc saltwas obtained.

    ______________________________________                                        Elemental Analysis:                                                                        C        H        N      S                                       ______________________________________                                        Calculated:  38.94    3.27     12.98  14.85                                   Found:       38.69    3.12     23.85  14.78                                   I.R.: N--H; 3.04, 3.13                                                           C=O; 5.91                                                                     N--O; 8.06                                                                 ______________________________________                                    

EXAMPLE 3 Preparation of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide

Step 1: 10.0 g (0.0578 mole) of 2-amino-6-bromopyridine was dissolved in40 ml dry pyridine and 6.4 ml (0.067 mole) of ethyl chloroformate wasadded dropwise while the solution was stirred and cooled in an ice-bathto maintain the reaction temperature at 15°-18° C. After 4 hours at roomtemperature, the reaction mixture was poured into 150 ml of ice waterand kept at 0° C overnight. Impure 2-ethoxycarbonylamino-6-bromopyridinewas obtained by filtration and subsequently recrystallized from 2:1methanol-water solution, giving an 88% yield of white solid,m.p.=70.2°-71.0° C.

    ______________________________________                                        Elemental Analysis:                                                                          C         H         N                                          ______________________________________                                        Calculated:    39.21     3.70      11.43                                      Found:         38.92     3.66      11.45                                      I.R.: N--H; 3.08                                                                 C=O; 5.85                                                                  ______________________________________                                    

Step 2: A suspension of 2.0 g (0.00816 mole) of2-ethoxycarbonylamino-6-bromopyridine in 10 ml of glacial acetic acidcontaining 1.3 ml (0.0102 mole) of 7.9M peracetic acid was heated at 70°C for 17 hours. The light yellow reaction mixture was cooled and dilutedwith 70 ml water and 8.5% unreacted2-ethoxycarbonylamino-6-bromopyridine was removed by filtration. Thesolution was concentrated in vacuo and the resultant viscous liquid wasdissolved in chloroform and extracted with saturated aqueous sodiumcarbonate and dried. The chloroform was removed in vacuo, leaving ayellow liquid which crystallized on standing. Impure2-ethoxycarbonylamino-6-bromopyridine-1-oxide was recrystallized fromcyclohexane, giving a 97.4% yield of off-white powder, m.p.=66.0°-67.5°C. A second recrystallization from cyclohexane raised the melting pointto 66.5°-67.5° C.

    ______________________________________                                        Elemental Analysis:                                                                          C         H         N                                          ______________________________________                                        Calculated:    36.80     3.47      10.73                                      Found:         37.12     3.53      10.78                                      IR: N--H; 3.02, 3.21                                                             C=0, 5.79                                                                     N--O; 7.92 or 8.25                                                         ______________________________________                                    

Step 3: A suspension of 1.3 g (0.0050 mole) of2-ethoxycarbonylamino-6-bromopyridine- 1-oxide in 17 ml (0.017 mole) of1M aqueous sodium hydrosulfide and 10 ml of ethanol was stirred at 65° Cfor 2 hours. The reaction mixture was cooled and filtered, giving a 78%yield of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide, a white product whichwas recrystallized from aqueous ethanol.

    ______________________________________                                        Elemental Analysis:                                                                         C       H        N      S                                       ______________________________________                                        Calculated:   40.68   3.84     11.86  13.57                                   Found:        40.93   3.75     11.88  14.29                                   IR: N--H; 3.10, 3.23                                                             C=O; 5.89                                                                     N--O; 7.79                                                                 ______________________________________                                    

EXAMPLE 4 Preparation of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide:

The procedure of Example 3 was repeated except that Step 2 relating tothe oxidation to the pyridine-oxide was changed, whereby a chloroformsolution of 2-ethoxycarbonylamino-6-bromopyridine was treated withm-chloroperbenzoic acid as the oxidizing agent for 9 days at roomtemperature, giving a 62% yield of2-ethoxycarbonylamino-6-bromopyridine-1-oxide.

EXAMPLE 5 Preparation of the zinc salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide:

0.236 g (0.00100 mole) of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide as prepared in Example3 or Example 4 was dissolved in 15 ml water and 2.6 ml (0.00052 mole) of0.20M aqueous zinc nitrate was added dropwise while stirring thesolution. A white solid precipitated immediately and was isolated byfiltration giving a 68% yield of the zinc salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide.

    ______________________________________                                        Elemental Analysis:                                                                          C        H       N     S                                       ______________________________________                                        Calculated:    39.07    3.69    11.39 13.04                                   Found:         39.91    3.95    11.80 12.72                                   IR: N--H; 3.01, 3.08, 3.05                                                       C=O; 5.78                                                                     N--O; 8.06                                                                 ______________________________________                                    

EXAMPLE 6

Preparation of Bis[2-(6-ethoxycarbonylamino-1-oxopyridyl)] disulfide:0.20 g (0.0084 mole) of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-1-oxide prepared in accordancewith either Example 3 or Example 4, was suspended in 8 ml water andstirred while adding 0.1M aqueous potassum triiodide until the yellowcolor of excess triiodide persisted. An 89% yield of impurebis[2-(6-ethoxycarbonylamino-1-oxopyridyl)] disulfide precipitated andwas recrystallized from acetonitrile to give a white solid,mp=186.0°-186.5° C.

    ______________________________________                                        Elemental Analysis:                                                                          C        H       N     S                                       ______________________________________                                        Calculated:    45.06    4.25    13.14 15.04                                   Found:         45.03    3.98    13.00 14.89                                   IR: N--H; 3.04, 3.11, 3.23                                                       C=O; 5.79                                                                     N--O; 8.02                                                                 ______________________________________                                    

EXAMPLE 7 Preparation of Bis[2-(6-acetamido-1-oxopyridyl)-disulfide]

A suspension of 0.40g (0.00217 mole) of2-acetamido-6-mercaptopyridine-1-oxide, prepared as in Example 1, in 5ml of water acidified to a pH of 2 with 2M aqueous hydrochloric acid,was stirred while adding: 0.1M aqueous potassium triiodide until apermanent yellow color of triiodide was evident. The reaction productwas filtered, giving a 70% yield of a tan product which was purified byrecrystallization from glacial acetic acid, m.p.=249.0°-250.0° C.

    ______________________________________                                        Elemental Analysis:                                                                        C        H        N      S                                       ______________________________________                                        Calculated:  45.89    3.85     15.29  17.50                                   Found:       45.52    3.72     15.35  18.43                                   IR: N--H; 3.20                                                                   C=O; 5.87                                                                     N--O; 8.00                                                                 ______________________________________                                    

EXAMPLE 8 Preparation of2-ethoxycarbonylamino-6-benzylthiopyridine-1-oxide

A suspension of 1.0 g (0.0038 mole) of2-ethoxycarbonylamino-6-bromopyridine-1-oxide, as prepared in Step 2 ofExample 3, in 25 ml of methanol containing equivalent amounts of benzylmercaptan and sodium methoxide, is heated under reflux for 2 hours. Thereaction mixture is diluted with 150 ml water and the impure product iscollected by filtration. Recrystallization from ethylacetate-cyclohexane gave white needles having a m.p. of 139.8°-140.2° C.

    ______________________________________                                        Elemental Analysis:                                                                        C        H        N      S                                       ______________________________________                                        Calculated:  59.19    5.30     9.20   10.53                                   Found:       59.45    5.32     9.26    9.97                                   IR: N--H; 3.04                                                                   C=O; 5.76                                                                     N--O; 7.95                                                                 ______________________________________                                    

From the elemental analysis and infrared spectral examination of thesubstituted amino-mercaptopyridine-oxide compounds and the intermediatesthereof, the structure of each compound with above examples has beenascertained.

EXAMPLE 9

    ______________________________________                                        Shampoo:                   %                                                  ______________________________________                                        Sodium salt of 2-ethoxycarbonylamino-6-mercapto-                                pyridine-1-oxide         1.0                                                Potassium hexadecyl sulfate                                                                              15.0                                               Sodium coco-fatty acid monoglycerine sulfate                                                             15.0                                               Coconut oil fatty acid diethanolamine                                                                    5.0                                                Lauric myristic monoethanolamide                                                                         3.0                                                Perfume                    1.0                                                Lanoline esters            1.0                                                Sodium carboxymethyl cellulose                                                                           0.2                                                Glycerine                  2.0                                                Water                      Balance                                            ______________________________________                                    

In lieu of the sodium salt of2-ethoxycarbonylamino-6-mercaptopyridine-oxide, other salts such as thezinc salt, or the acylamino mercapto compound per se may be utilized.Similarly beneficial results are also obtainable by utilizing othershampoo formulations, based on nonionic or cationic detergents or otherof the previously mentioned synthetic detergents instead of thementioned combination of anionic detergents. A similar result is notedwhen the shampoo is based on soluble higher fatty acid soap. Usually,for shampoo applications, the milder of the mentioned detergents will beselected, so as to avoid unduly drying or embrittling the hair.

10

    ______________________________________                                        Hairdressings:             %                                                  ______________________________________                                        (A)                                                                           Light mineral oil          72.0                                               Isopropyl myristate        22.0                                               Lanolin                    2.0                                                Lanolin esters             1.5                                                Perfume                    1.2                                                Sodium salt of 2-acetamide-6-mercaptopyridine-                                  1-oxide                  1.3                                                (B)                                                                           Light mineral oil, white deodorized                                                                      45.0                                               Stearic acid               5.0                                                Cetyl alcohol              2.0                                                Triethanoamine             2.5                                                Perfume                    0.7                                                Zinc salt of 2-acetamide-6-mercaptopyridine-                                    1-oxide                  2.0                                                Water                      42.8                                               ______________________________________                                    

Approximately three cubic centimeters per application is used intreating human hair and scalp. This treatment may be repeated daily overa period of weeks. The compositions are especially useful with respectto diminishing fungal and bacterial counts and are particularlyeffective against Pityrosporum ovale, the yeast most frequentlyassociated with dandruff, even in the presence of the sebum normallyfound on the hair and scalp.

In place of the particular salts of2-acetamido-6-mercaptopyridine-1-oxide of the above formulas, similarproportions, or variations in proportions within the ranges described inthe specification, of other salts, e.g., the copper, nickel, chromium,trimethylcetyl ammonium, ammonium, alkanolamine and other such salts,may be employed to obtain substantially similar antimicrobialactivities. It is noted that the bactericides are especially useful evenin the normally oily environment of the scalp and hair and in thelipophilic phases of hairdressings.

Similar results are obtained when the mentioned bactericides are used insimilar proportions in other cosmetics, e.g., hair setting compositions,"aerosol" hair sprays, hair dyes, skin creams, talcum powders and footpowders.

The invention has been described with respect to various illustrationsand embodiments thereof. However, the invention is broader than theillustrations given and it will be evident to one of ordinary skill inthe art that substitutes and equivalents may be employed within theinventive concept.

What is claimed is:
 1. A disulfide of mercaptopyridine-1-oxide havingthe following structural formula: ##STR10## wherein R is selected fromthe group consisting of the acyl radical R_(o) C═O and thealkoxycarbonyl radical R_(o) --OC═O, where R_(o) is a C₁ -C₆ alkyl, arylselected from the class consisting of phenyl or naphthyl, or aralkyl,said alkyl portion having 1-6 carbons, or halobenzyl, the C₁ -6 alkanesulfonyl radical, the aralkanesulfonyl radical, and the arenesulfonylradical ArSO₂ wherein the aryl radical may be substituted by a C₁ -C₆alkyl, alkoxy and/or a halo-radical; R₁, R₂ and R₃ are eachindependently selected from the group consisting of hydrogen, methyl,two of said terms may represent methoxy and the other hydrogen, and oneof said terms may represent ethyl, n-butyl, methoxy, ethoxy, phenyl,bromophenyl, chlorophenyl, trichlorophenyl, naphthyl, chlorobenzyl,dichlorobenzyl or furyl and the other two terms represent hydrogen.
 2. Acompound according to claim 1, wherein R₁, R₂ and R₃ are all hydrogen.3. A compound according to claim 1, which is the disulfide of a2-acylamino-6-mercaptopyridine-1-oxide.
 4. A compound according to claim1, which is the disulfide of a2-alkoxycarbonylamino-6-mercaptopyridine1-oxide.
 5. A compound accordingto claim 4, which is bis[2-(6-ethoxycarbonylamino-1-oxopyridyl)]disulfide.
 6. A compoundaccording to claim 3, which is bis[2-(6-acetamido-1-oxopyridyl)]disulfide.